The rapid pace of disease gene discovery, fueled by the Human Genome Project, has in turn fueled a continuous expansion in the number of analytes tested by molecular diagnostic laboratories, especially those involved in heritable disease testing. Some have questioned whether the time interval from gene discovery to clinical test translation may be shorter than desired for full understanding of the test's clinical utility.
Yet even if that need were satisfied, the speed of new test development and the sheer number of genes and mutations targeted for analysis have led to another bottleneck: the lack of well-characterized control materials containing mutations of interest (Williams et al. Arch. Pathol. Lab. Med. 127:1353-8, 2003). These materials are used as positive controls in the assays, for test research and development, for test validation and evaluation, and as resources for quality assurance programs such as the nationwide and international proficiency testing programs offered jointly by the College of American Pathologists (CAP) and the American College of Medical Genetics (ACMG) (Grody, Diagn. Molec. Pathol. 3:221-3, 1994; Dequeker et al. Nature Rev. Genet. 2:717-23, 2001; Richards and Grody, Clin. Chem. 49:717-8, 2003) and performance evaluation programs offered by CDC (see the Model Performance Evaluation Program (MPEP) on the CDC website).
Procurement of these control materials from natural sources is hampered by the rarity of many target mutations, the limited quantity in clinical specimens, the dependence on clinicians to recognize the need and take the initiative to deposit patient samples in existing repositories (such as the Coriell Institute), and regulatory governing such as informed consent, sample ownership, and genetic privacy. The lack of easily accessible, validated mutant controls has proven to be a major obstacle to the advancement of clinical molecular genetic testing. Therefore, there is a need for alternative controls that can serve this purpose.